Effects of serotonin 5-HT3 receptor antagonists on CRF-induced abnormal colonic water transport and defecation in rats

Hirata, Tetsuya; Keto, Yoshihiro; Nakata, Mari; Takeuchi, Asako; Funatsu, Toshiyuki; Akuzawa, Shinobu; Sasamata, Masao; Miyata, Keiji

doi:10.1016/j.ejphar.2008.03.040

Cited by 16 publications

(10 citation statements)

References 20 publications

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“…Activation of 5-HT 2A receptors elicits colonic secretion. Likewise, 5-HT 3 stimulation evokes chloride secretion, whereas 5-HT 3 antagonists blunt 5-HT-mediated colonic secretion in response to cholera toxin, GI pathogens, and corticotropin releasing factor [13,14]. 5-HT 4 activation elicits chloride and bicarbonate secretion from intestinal and colonic epithelia.…”

Section: Intestinal Secretionmentioning

confidence: 97%

Serotonin and the GI tract

Hasler

2009

Curr Gastroenterol Rep

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Serotonin (5-hydroxytryptamine, 5-HT) participates in several functions of the gastrointestinal tract. Receptors in seven families (5-HT(1)-5-HT(7)) were identified, many of which are present on enterocytes, intrinsic and extrinsic neurons, interstitial cells, and gut myocytes. Most 5-HT is released from enterochromaffin cells in response to physiologic and pathologic stimuli. Roles of 5-HT in health include control of normal gut motor activity, secretion, and sensation, and regulation of food intake and cell growth. Abnormalities of serotonergic function contribute to symptom genesis in functional bowel disorders, inflammatory and infectious diseases of the gut, emetic responses to varied stimuli, obesity, and dysregulation of cell growth. Therapies acting as agonists or antagonists of 5-HT receptors or that modulate 5-HT reuptake play prominent roles in managing these conditions, although use of many agents is hampered by cardiopulmonary complications. Novel agents are in testing, which may exhibit efficacy without significant toxicity.

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Section: Intestinal Secretionmentioning

confidence: 97%

Serotonin and the GI tract

Hasler

2009

Curr Gastroenterol Rep

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“…Ramosetron tended to improve abdominal discomfort and/or pain even at a dose of 1 µg, which did not improve stool condition. This suggests the possibility that ramosetron has a direct inhibitory effect on abdominal discomfort and/or pain, and corresponds to the results of other 5-HT 3 receptor antagonists [2, 3]. As ramosetron has both an improving effect on stool condition and on abdominal discomfort and/or pain, the drug is considered to satisfy the essential qualification for a therapeutic drug for IBS.…”

Section: Discussionmentioning

confidence: 99%

“…Ramosetron also inhibited an acceleration of defecation induced by conditioned fear stress, which is assumed to be psychological stress [7, 8]. Moreover, ramosetron inhibited an acceleration of defecation by CRH [2]. On the other hand, it is suggested that ramosetron does not inhibit defecation abnormality induced by prostaglandin and castor oil or spontaneous defecation, but only inhibits acceleration of defecation or diarrhea induced by stress [6, 8, 9].…”

Section: Introductionmentioning

confidence: 99%

“…In the intestinal nerves, 5-HT acts on the 5-HT 3 receptors on parasympathetic ganglia to cause the contraction of intestinal smooth muscle and an increase in intestinal secretion by stimulating acetylcholine release from nerve terminals. 5-HT 3 receptor antagonists have been reported to inhibit the accelerated colonic transit, abnormal colonic water transport, defecation abnormality (increased defecation and diarrhea), and the lowered colonic perceptual threshold by corticotropin-releasing hormone (CRH) or stress in animals [1,2,3], which suggested the involvement of 5-HT 3 in the pathophysiology of irritable bowel syndrome (IBS). Accordingly, 5-HT 3 receptor antagonists are expected to improve stress-induced motility dysfunction in the lower gastrointestinal tract, including IBS in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

Matsueda

Harasawa²,

Hongo

et al. 2008

Digestion

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Background: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder. Serotonin type 3 (5-HT₃) receptor antagonist alosetron hydrochloride is indicated for women with chronic, severe diarrhea-predominant IBS who have not responded adequately to conventional therapy. However, whether or not the therapeutic efficacy of 5-HT₃ receptor antagonists has gender difference is uncertain. Methods: A double-blind, placebo-controlled, parallel-group, comparative study was conducted to evaluate the effect of novel 5-HT₃ receptor antagonist, ramosetron hydrochloride, in male and female patients with diarrhea-predominant IBS. 418 subjects were randomized (109 subjects: placebo, 105 subjects: 1 µg, 103 subjects: 5 µg, and 101 subjects: 10 µg) and administered the study drug once daily. Results: The monthly responder rates of ‘Patient-reported global assessment of relief of irritable bowel syndrome symptoms’ in the 5- and 10-µg ramosetron hydrochloride-administered groups were higher than the placebo group (26.92, 42.57, and 43.01% for placebo, 5 and 10 µg). Moreover, the difference of the responder rate in comparison with the placebo group was similar in males and females. As for safety, there was tolerability at doses up to 10 µg. Conclusion: Ramosetron is an effective and well-tolerated treatment not only for female IBS patients but also for male patients.

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“…61 First, CRF and Ucn1 injected into the cerebrospinal fluid induces the occurrence of colonic spike burst activity, acceleration of colonic transit, decreased in colonic fluid absorption, stimulation of defecation, and induction of diarrhea in freely moving rats, mice and gerbils, mimicking the effects of exposure to acute stressors whereas Ucn2 and Ucn3 under the same conditions have no effect. [72][73][74][75][76][77][78][79][80] Brain nuclei responsive to CRF leading to the stimulation of colonic motor function (increased in tonic and phasic colonic motility, decreased colonic transit time and induction of watery fecal output) have been localized in the hypothalamus (PVN, arcuate nucleus) and pontine areas, namely the locus coeruleus (LC)/ Barrington nucleus complex, [93][94][95][96] which are also brain nuclei involved in central CRF-induced anxiety and depression. 97,98 Anatomical support for the role of pontine and PVN CRF signaling pathways in the regulation of pelvic organ functions came from tracing studies showing that a proportion of CRF immunoreactive neurons in the Barrington's nucleus and PVN are linked transynaptically to the colon.…”

Section: Activation Of Brain Corticotropin-releasing Factor Receptor mentioning

confidence: 99%

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

Taché¹,

Million²

2015

J Neurogastroenterol Motil

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The corticotropin-releasing factor (CRF) signaling systems encompass CRF and the structurally related peptide urocortin (Ucn) 1, 2, and 3 along with 2 G-protein coupled receptors, CRF1 and CRF2. CRF binds with high and moderate affinity to CRF1 and CRF2 receptors, respectively while Ucn1 is a high-affinity agonist at both receptors, and Ucn2 and Ucn3 are selective CRF2 agonists. The CRF systems are expressed in both the brain and the colon at the gene and protein levels. Experimental studies established that the activation of CRF1 pathway in the brain or the colon recaptures cardinal features of diarrhea predominant irritable bowel syndrome (IBS) (stimulation of colonic motility, activation of mast cells and serotonin, defecation/watery diarrhea, and visceral hyperalgesia). Conversely, selective CRF1 antagonists or CRF1/CRF2 antagonists, abolished or reduced exogenous CRF and stress-induced stimulation of colonic motility, defecation, diarrhea and colonic mast cell activation and visceral hyperalgesia to colorectal distention. By contrast, the CRF2 signaling in the colon dampened the CRF1 mediated stimulation of colonic motor function and visceral hyperalgesia. These data provide a conceptual framework that sustained activation of the CRF1 system at central and/or peripheral sites may be one of the underlying basis of IBS-diarrhea symptoms. While targeting these mechanisms by CRF1 antagonists provided a relevant novel therapeutic venue, so far these promising preclinical data have not translated into therapeutic use of CRF1 antagonists. Whether the existing or newly developed CRF1 antagonists will progress to therapeutic benefits for stress-sensitive diseases including IBS for a subset of patients is still a work in progress.

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Effects of serotonin 5-HT3 receptor antagonists on CRF-induced abnormal colonic water transport and defecation in rats

Cited by 16 publications

References 20 publications

Serotonin and the GI tract

Serotonin and the GI tract

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

Role of Corticotropin-releasing Factor Signaling in Stress-related Alterations of Colonic Motility and Hyperalgesia

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